Surface Modification of Polymeric Nanoparticles with M2pep Peptide for Drug Delivery to Tumor-Associated Macrophages

Abstract

Purpose

Tumor-associated macrophages (TAMs) with immune-suppressive M2-like phenotype constitute a significant part of tumor and support its growth, thus making an attractive therapeutic target for cancer therapy. To improve the delivery of drugs that control the survival and/or functions of TAMs, we developed nanoparticulate drug carriers with high affinity for TAMs.

Methods

Poly(lactic-co-glycolic acid) nanoparticles were coated with M2pep, a peptide ligand selectively binding to M2-polarized macrophages, via a simple surface modification method based on tannic acid-iron complex. The interactions of M2pep-coated nanoparticles with macrophages of different phenotypes were tested in vitro and in vivo. PLX3397, an inhibitor of the colony stimulating factor-1 (CSF-1)/CSF-1 receptor (CSF-1R) pathway and macrophage survival, was delivered to B16F10 tumors via M2pep-modified PLGA nanoparticles.

Results

In bone marrow-derived macrophages polarized to M2 phenotype, M2pep-coated nanoparticles showed greater cellular uptake than those without M2pep. Consistently, M2pep-coated nanoparticles showed relatively high localization of CD206+ macrophages in B16F10 tumors. PLX3397 encapsulated in M2pep-coated nanoparticles attenuated tumor growth better than the free drug counterpart.

Conclusion

These results support that M2pep-coating can help nanoparticles to interact with M2-like TAMs and facilitate the delivery of drugs that control the tumor-supportive functions of TAMs.

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References

  1. 1.

    Egeblad M, Nakasone ES, Werb Z. Tumors as organs: complex tissues that interface with the entire organism. Dev Cell. 2010;18(6):884–901.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B, et al. A perivascular niche for brain tumor stem cells. Cancer Cell. 2007;11(1):69–82.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Cirri P, Chiarugi P. Cancer associated fibroblasts: the dark side of the coin. Am J Cancer Res. 2011;1(4):482–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell. 2009;139(5):891–906.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41(1):49–61.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Bingle L, Brown NJ, Lewis CE. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol. 2002;196(3):254–65.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Qian B, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141(1):39–51.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4(1):71–8.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Sawawejksza K, Kandeferszerszeń M. Tumor-associated macrophages as target for antitumor therapy. Arch Immunol Ther Ex. 2018;66(2):97–111.

    CAS  Article  Google Scholar 

  10. 10.

    Mantovani A, Schioppa T, Porta C, Allavena P, Sica A. Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metast Rev. 2006;25(3):315–22.

    Article  Google Scholar 

  11. 11.

    Leuschner F, Dutta P, Gorbatov R, Novobrantseva TI, Donahoe JS, Courties G, et al. Therapeutic siRNA silencing in inflammatory monocytes in mice. Nat Biotechnol. 2011;29(11):1005–10.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Zanganeh S, Hutter G, Spitler R, Lenkov O, Mahmoudi M, Shaw A, et al. Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues. Nat Nanotechnol. 2016;11(11):986–94.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Gan J, Dou Y, Li Y, Wang Z, Wang L, Liu S, et al. Producing anti-inflammatory macrophages by nanoparticle-triggered clustering of mannose receptors. Biomaterials. 2018;178:95–108.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Rodell CB, Arlauckas SP, Cuccarese MF, Garris CS, Li R, Ahmed MS, et al. TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy. Nat Biomed Eng. 2018;2:578–88.

    PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Cory TJ, He H, Winchester LC, Kumar S, Fletcher CV. Alterations in P-glycoprotein expression and function between macrophage subsets. Pharm Res. 2016;33(11):2713–21.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Qian Y, Qiao S, Dai Y, Xu G, Dai B, Lu L, et al. A molecular-targeted immunotherapeutic strategy for melanoma via dual-targeting nanoparticles delivering small interfering RNA to tumor-associated macrophages. ACS Nano. 2017;11(9):9536–49.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Turk MJ, Waters DJ, Low PS. Folate-conjugated liposomes preferentially target macrophages associated with ovarian carcinoma. Cancer Lett. 2004;213(2):165–72.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Movahedi K, Schoonooghe S, Laoui D, Houbracken I, Waelput W, Breckpot K, et al. Nanobody-based targeting of the macrophage mannose receptor for effective in vivo imaging of tumor-associated macrophages. Cancer Res. 2012;72(16):4165–77.

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Maryelise C, Jingjing T, Yu JL, Hua C, Maja Z, Koka M, et al. Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival. Proc Natl Acad Sci U S A. 2013;110(40):15919–24.

    Article  Google Scholar 

  20. 20.

    Ngambenjawong C, Cieslewicz M, Schellinger JG, Pun SH. Synthesis and evaluation of multivalent M2pep peptides for targeting alternatively activated M2 macrophages. J Control Release. 2016;224:103–11.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Ngambenjawong C, Pun SH. Multivalent polymers displaying M2 macrophage-targeting peptides improve target binding avidity and serum stability. Acs Biomater Sci Eng. 2017;3(9):2050–3.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Abouelmagd SA, Meng F, Kim BK, Hyun H, Yeo Y. Tannic acid-mediated surface functionalization of polymeric nanoparticles. ACS Biomater Sci Eng. 2016;2(12):2294–303.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Park J, Brust TF, Lee HJ, Lee SC, Watts VJ, Yeo Y. Polydopamine-based simple and versatile surface modification of polymeric nano drug carriers. ACS Nano. 2014;8(4):3347–56.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Han N, Pang L, Xu J, Hyun H, Park J, Yeo Y. Development of surface-variable polymeric nanoparticles for drug delivery to tumors. Mol Pharm. 2017;14(5):1538–47.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Sileika TS, Barrett DG, Zhang R, Lau KHA, Messersmith PB. Colorless multifunctional coatings inspired by polyphenols found in tea, chocolate, and wine. Angew Chem Int Ed Engl. 2013;52(41):10766–70.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Hong S, Yeom J, Song IT, Kang SM, Lee H, Lee H. Pyrogallol 2-Aminoethane: a plant flavonoid-inspired molecule for material-independent surface chemistry. Adv Mater Interfaces. 2014;1:1400113.

    Article  Google Scholar 

  27. 27.

    Wedege E, Svenneby G. Effects of the blocking agents bovine serum albumin and tween 20 in different buffers on immunoblotting of brain proteins and marker proteins. J Immunol Methods. 1986;88(2):233–7.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Hyun H, Park J, Willis K, Park JE, Lyle LT, Lee W, et al. Surface modification of polymer nanoparticles with native albumin for enhancing drug delivery to solid tumors. Biomaterials. 2018;180:206–24.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Shin M, Lee HA, Lee M, Shin Y, Song JJ, Kang SW, et al. Targeting protein and peptide therapeutics to the heart via tannic acid modification. Nat Biomed Eng. 2018;2(5):304–17.

    Article  Google Scholar 

  30. 30.

    Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000prime Rep. 2014;6:13.

    PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122(3):787–95.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883–99.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Chamberlain LM, Holtcasper D, Gonzalezjuarrero M, Grainger DW. Extended culture of macrophages from different sources and maturation results in a common M2 phenotype. J Biomed Mater Res A. 2015;103(9):2864–74.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Kroner A, Greenhalgh A, Zarruk J, Passosdossantos R, Gaestel M, David S. TNF and increased intracellular Iron Alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord. Neuron. 2014;83(5):1098–116.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Balkwill FR, Capasso M, Hagemann T. The tumor microenvironment at a glance. J Cell Sci. 2012;125:5591–6.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Zhao P, Yin W, Wu A, Tang Y, Wang J, Pan Z, et al. Dual-targeting to Cancer cells and M2 macrophages via biomimetic delivery of Mannosylated albumin nanoparticles for drug-resistant Cancer therapy. Adv Funct Mater. 2017;27(44):1700403.

    Article  Google Scholar 

  37. 37.

    Leonard F, Curtis LT, Yesantharao P, Tanei T, Alexander JF, Wu M, et al. Enhanced performance of macrophage-encapsulated nanoparticle albumin-bound-paclitaxel in hypo-perfused cancer lesions. Nanoscale. 2016;8(25):12544–52.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Kumari A, Silakari O, Singh RK. Recent advances in colony stimulating factor-1 receptor/c-FMS as an emerging target for various therapeutic implications. Biomed Pharmacother. 2018;103:662–79.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Ries CH, Cannarile MA, Hoves S, Benz J, Wartha K, Runza V, et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for Cancer therapy. Cancer Cell. 2014;25(6):846–59.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Hume DA, Macdonald KPA. Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling. Blood. 2012;119(8):1810–20.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. 2013;19(10):1264–72.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Park J, Sun B, Yeo Y. Albumin-coated nanocrystals for carrier-free delivery of paclitaxel. J Control Release. 2017;263:90–101.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Mok S, Tsoi J, Koya RC, Hulieskovan S, West BL, Bollag G,et al. Inhibition of colony stimulating factor-1 receptor improves antitumor efficacy of BRAF inhibition. BMC Cancer. 2015;15(1):356.

    PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Mok S, Koya RC, Tsui C, Xu J, Robert L, Wu L,et al. Inhibition of CSF-1 receptor improves the antitumor efficacy of adoptive cell transfer immunotherapy. Cancer Res. 2014;74(1):153–61.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Yan D, Kowal J, Akkari L, Schuhmacher AJ, Huse JT, West BL, et al. Inhibition of colony stimulating factor-1 receptor abrogates microenvironment-mediated therapeutic resistance in gliomas. Oncogene. 2017;36(43):6049–58.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Shen S, Li HJ, Chen KG, Wang YC, Yang XZ, Lian ZX, et al. Spatial targeting of tumor-associated macrophages and tumor cells with a pH-sensitive cluster Nanocarrier for Cancer Chemoimmunotherapy. Nano Lett. 2017;17(6):3822–9.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Alvey CM, Spinler KR, Irianto J, Pfeifer CR, Hayes B, Xia Y, et al. SIRPA-inhibited, marrow-derived macrophages engorge, accumulate, and differentiate in antibody-targeted regression of solid tumors. Curr Biol. 2017;27(14):2065–77.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Song D, Zhao J, Deng W, Liao Y, Hong X, Hou J. Tannic acid inhibits NLRP3 inflammasome-mediated IL-1β production via blocking NF-κB signaling in macrophages. Biochem Biophys Res Commun. 2018;503(4):3078–85.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Xu X, Guo Y, Zhao J, He S, Wang Y, Lin Y, et al. Punicalagin, a PTP1B inhibitor, induces M2c phenotype polarization via up-regulation of HO-1 in murine macrophages. Free Radic Biol Med. 2017;110:408–20.

    CAS  PubMed  Article  Google Scholar 

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Acknowledgments and Disclosures

This work was supported by NIH R01 EB017791, NIH R01 CA232419, and the fellowship support from the China Scholarship Council Fellowship to L.P.

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Correspondence to Yoon Yeo.

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Pang, L., Pei, Y., Uzunalli, G. et al. Surface Modification of Polymeric Nanoparticles with M2pep Peptide for Drug Delivery to Tumor-Associated Macrophages. Pharm Res 36, 65 (2019). https://doi.org/10.1007/s11095-019-2596-5

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KEY WORDS

  • Drug delivery
  • M2pep
  • PLGA nanoparticles
  • PLX3397
  • tumor-associated macrophages